Discussion
This study provides experimental evidence of a series of synaptic
alterations of the lateral and the medial perforant paths in response to
the transient hypofunction of NMDARs. We documented persistent
dysregulation in the glutamate release process from the LPP synapse,
blunted induction of LPP LTP, and decreased synaptic filtering
capability. In the MPP-DG synapse, the altered glutamate release was
accompanied by impaired CB1R-dependent LTD and weakened
LTP. Mechanistically, the impairment of MPP LTD was partly due to
decreased functional expression of the CB1R. More
importantly, enhancing the 2-AG signaling pathway via pharmacological
inhibition of the MAGL enzyme restored the strength of the MPP LTD. At
the behavioral level, we show for the first time that transient
hypofunction of NMDARs impairs spatial discrimination, a cognitive task
in which DG plays a critical role.